DESCRIPTION (Adapted from the application) The overall goal of this project is to understand the signal network contributing to the homeostasis of prostate gland. The prostate gland is an exquisitely androgen-dependent organ, in particular, the prostatic epithelium. The luminal epithelium requires androgen for maintaining its cell architecture and normal physiologic function; it undergoes apoptosis with androgen deprivation. In contrast, the basal epithelium, an androgen-independent (AI) cell population, remains in the degenerated gland and can fully regenerate the entire gland back to normal pre-programmed size in the presence of androgen administration. Therefore, the basal cell population may represent a stem cell population and homeostatic signal(s) in these cells play a critical role in controlling growth/differentiation of prostatic epithelium. Recent results suggest that the pathologic hyperplastic condition is often detected in the basal cell population of prostate and the relapse of Al prostate cancer may well be derived from a stem cell population. It is conceivable that the altered homeostatic factors mark the first event leading to prostate pathogenesis. However, the nature of these signals has not been well defined. Using differential display polymerase chain reactions (PCR), we were able to clone a cDNA sequence (i.e., DOC2) from an enriched prostate stem cell population of degenerated prostate. Sequencing data provide compelling evidence suggesting the DOC2 as a novel signal molecule. Our preliminary data indicated that decreased DOC2 protein is frequently detected in prostate cancer cell lines and patients? specimen as well. We also demonstrated that DOC2 is a potent growth suppressor in the prostatic epithelial cells from in vitro. We have further demonstrated that DOC2 protein function can be modulated by its protein phosphorylation and the interaction with a new member of GTPase activating protein family, indicating that DOC2 represents a critical regulatory element in controlling the signaling pathway(s) leading to the growth/differentiation of prostatic epithelium. Based on these findings, in this application, we plan to determine the profile of DOC2 and DIP expression during fetal prostate development and correlate DOC2 levels between pathologic hyperplasia and cancer progression. Subsequently, we will determine the functional domain of DOC2 contributing for the growth inhibition of prostate cancer in vitro and in vivo. To define the mechanism of action of DOC2, we will examine the interaction of DOC2 and DIP molecules in prostatic epithelium. Finally, we would like to explore the possibility that whether both DOC2 and DIP can be potent therapeutic agents. The outcome of these results could have a significant impact on our understanding of the fundamentals of prostate homeostasis and further lead to the novel and more effective intervention to the prostate pathogenesis.